Process and apparatus for producing inhalable medicaments

ABSTRACT

A method for crystallizing a substance, especially an inhalable medicament, comprising the following steps:  
     (a) dissolving said substance in a solvent, to produce a solution of said substance,  
     (b) producing a segmented stream which consists of alternating segments of said solution of the substance and of a transport medium,  
     (c) introducing said segmented stream into the first end of a retention stretch, which retention stretch has a first end and a second end, so that said segmented stream passes from said first end to said second end of said retention stretch, and exists from the second end of the retention stretch,  
     (d) cooling the retention stretch, to thereby bring about crystallization of the substance in the segments of solution, in the segmented stream, as said segmented stream passes through the retention stretch, and  
     (e) separating the crystals of material from the segmented stream as it exits from the second end of the retention stretch.  
     Also disclosed is an apparatus for carrying out the method.

BACKGROUND OF THE INVENTION

[0001] 1. Technical Field

[0002] The invention relates to a process for the continuous productionof inhalable medicaments and to an apparatus for carrying out theprocess.

[0003] 2. Background Information

[0004] Within the framework of the invention, the term “medicament”refers to the active component of a medicament which is commonly alsoreferred to as the psychopharmacological agent or active ingredient.

[0005] Inhalatives require a certain form of the medicament. Forexample, micronised medicaments or active ingredients generally come insolid form. In order to guarantee the inhalability of the medicament,high requirements are placed on the particle size, the particle sizedistribution, the morphology, the stability and the flow performance.

[0006] In general, the entire administered dose of the medicament doesnot reach the lungs, rather only a part of this does. The particle sizehas a substantial influence on the proportion of the medicament whichactually reaches the lungs. For this reason, particles are preferredwhich have a diameter of less than 20 μm, preferably less than 5 μm andgreater than 0.3 μm. The diameter of the particle should be within thegiven window and furthermore should have the narrowest possible sizedistribution. Larger particles are separated off during respiration inthe upper airways whilst smaller particles are not deposited in thelungs and these leave again when exhaling.

[0007] Within the framework of the present invention, particle diametermeans the aerodynamic particle diameter wherein this is defined as theequivalent diameter of a ball of density 1 g/cm³ which has the samesedimentation speed in air as the examined particle.

[0008] Furthermore, high requirements are placed on the physicalstability of the micronised medicament particles. Particles shouldpreferably exist in stable crystalline form with environmentalconditions, to prevent agglomeration by phase transition. The stabilityof the medicament particles thus has indirect influence on the actualquantity of medicaments which reaches the lungs. For this reason, highrequirements are placed on the stability of the medicament in order toguarantee consistent quality, especially a particle size or sizedistribution of the medicament which is constant over time. This qualityfeature is indispensable in the field of pharmacy and in the use ofmedicaments because the effect of the medicament depends on the dosewhich reaches the lungs and thus, as described above, on the particlesize and its size distribution.

[0009] The same applies for morphology of the micronised particles sincethe nature of the particle surface has a direct influence on theinclination of the particle towards agglomeration and thus indirectinfluence on the particle size itself or the durability of themedicament.

[0010] Adjuvants can be added to the micronised medicament, allowing thephysico-chemical characteristics of a medicament to be set, whereinthese influence the quality-determining parameters such asbio-availability, effectiveness and durability in a desired manner.

[0011] Apart from the particle size and the size distribution of themicronised medicament, the type, particle size and quantity ratio of theadded adjuvant can decisively influence the medicament dose whichreaches the lungs.

[0012] Conventional processes for producing inhalable medicaments aregenerally two-stage, when considered from a roughly-structuredviewpoint, wherein in a first stage, the medicament is produced in asolid, generally crystalline form which is transformed into micronisedparticles in a second stage within the framework of a comminutionprocess. Accordingly to the prior art, milling processes can be used forthe comminution process, wherein in particular air-jet milling hasattained great significance since it is economical, can be used for amultitude of substances and allows simple separation of the desiredparticle fractions by means of a downstream cyclone separator.

[0013] The disadvantage with the air-jet milling used according to theprior art is that the solid material particles are principally subjectedto a considerable force effect during the milling process. This forceeffect induces considerable local heating and moreover leads to theformation of amorphous portions. As a result of the local heating,air-jet milling or milling as a comminution process in general is notsuitable for low-melting, thermally unstable or denaturisable materials.

[0014] Furthermore, when storing jet-milled medicaments, agglomerationis often observed since the amorphous portions resulting from themilling process re-crystallise.

BRIEF SUMMARY OF THE INVENTION

[0015] On this basis, the object of the present invention is to providea process for the continuous production of inhalable medicaments whereit is ensured that the aforementioned requirements of medicaments aremaintained, and furthermore the disadvantages of the process usedaccording to the prior art are avoided.

[0016] Furthermore, a partial object of the present invention is toprovide an apparatus for carrying out the process according to theinvention.

[0017] A further partial object of the present invention is to provide amedicament which fulfils the requirements of inhalable medicaments,especially the requirements of particle size, particle distribution,morphology and stability.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018]FIG. 1 is a diagram depicting the concentration vs. temperature ofa solution entering the retention stretch of the apparatus according tothe invention.

[0019]FIG. 2 depicts the temperature control T(t) of an embodiment ofthe process according to the invention for setting a constantoversaturation ΔC(t).

[0020]FIG. 3 is a schematic embodiment of a micro-reactor forimplementing the process of the invention.

[0021]FIG. 4 depicts a micro-mixer of the micro-reactor according to afirst embodiment of the apparatus according to the invention, incross-section.

[0022]FIG. 4a is an enlargement of the structures of the channels of themicro-mixer shown in FIG. 4.

[0023]FIG. 5 depicts a segmenter of the micro-reactor according to afirst embodiment, in cross-section.

[0024]FIG. 6 depicts a micro-mixer of the micro-reactor according to asecond embodiment with integrated segmenter, in cross-section.

[0025]FIG. 7 depicts a segmenter of the micro-reactor according to athird embodiment, in cross-section.

[0026]FIG. 8 depicts a segmenter of the micro-reactor according to afourth embodiment, in cross-section.

[0027]FIG. 9 depicts the retention stretch of an embodiment of amicro-reactor, in cross-section, with the two-phase flow guided in theretention stretch.

[0028]FIG. 10 depicts a retention stretch of an embodiment of amicro-reactor with the temperature courses over the length of theretention stretch and over time.

DETAILED DESCRIPTION OF THE INVENTION

[0029] The object, based on the process, is solved by a continuousprocess for the production of inhalable medicaments which has thefollowing procedural steps:

[0030] use of a medicament solution,

[0031] segmenting the solution by means of a segmenter and a transportmedium,

[0032] induction and guidance of the crystallisation process in aretention stretch by subjecting it to a defined temperature wherein theseed formation process is first induced by means of a rapid temperaturereduction in such a way that the solution adopts an oversaturated,meta-stable or unstable state with regard to the temperature T and theconcentration C of the material dissolved therein, and following thiscrystal growth is influenced by intentional cooling, and

[0033] separating off the crystal particles from the remaining phases ina separator after passing through the retention stretch.

[0034] In accordance with the invention, a medicament solution is usedas a starting point. Existing medicament solutions can be used, forexample a solution which precipitates during the production of themedicament.

[0035] This solution is then supplied to a segmenter and is segmentedwith a transport medium. The transport medium is a second fluid which isimmiscible with the solution and with the help of which the solution isdivided into the form of separate segments in such a way that theseparate segments, which are preferably of the same volume, are insertedinto a carrier stream comprising the transport medium. The transportmedium can be gaseous or fluid, wherein it has proven to be the case inthe tests that air saturated with solvent vapour of the solvent isespecially suitable as a transport medium. The two streams which aresupplied to the segmenter, i.e. the solution on the one hand and thetransport medium on the other hand, leave the segmenter as a segmented,preferably uniformly segmented, two-phase stream.

[0036] The dimensions of the segmenter channels of the segmenter whichis preferably to be used for the process of the invention lie in therange of 0.1 mm to 5 mm, preferably between 0.2 and 1 mm. Hence theseare therefore smallest structures.

[0037] Furthermore, the segmenter can be constructively shaped so thatits temperature can be easily controlled, that is, it can be easilyheated/cooled and great cooling rates—temperature difference per timeunit—can be attained. This is supported by the formation of smalleststructures.

[0038] Furthermore, the flow rate of the solution and transport mediumcan be varied within wide boundaries, whereupon it is possible todirectly influence the formation and thus the shape of the segmentedtwo-phase flow. This can preferably be set so that approximatelyequivalently-sized fluid segments with a length of two to three timesthe channel diameter can be produced.

[0039] After segmentation, the segmented two-phase flow is supplied to aretention stretch. The retention stretch serves for actual production ofthe inhalable medicament or the particles which are to be produced withthe aforementioned characteristics with regard to particle size, sizedistribution of the particles, morphology and stability.

[0040] When the two-phase flow enters the retention stretch, in a firststep the seed formation process is induced by a sharp reduction intemperature. We refer to FIG. 1, which shows theconcentration/temperature diagram of the solution, for furtherexplanation of the processes which take place in the retention stretch.Two curves are drawn in the quadrant between the y axis (concentration)and the x axis (temperature) one of which is solid and one which isdotted, and through which three different areas are formed.

[0041] The first area is on the right of the solid line, is thereforelimited by this on the left, and represents the area of the unsaturatedsolution in which neither a seed formation process or crystal growthtakes place. Crystal growth, which always requires the prior formationof a seed, basically only takes place in an oversaturated solution sincealready-formed crystals principally return into solution, at least inpart, when crossing the saturation line (solid line).

[0042] The area of the oversaturated solution on the left of the solidline can again be divided into two areas wherein the area between thetwo lines forms the meta-stable zone in which crystal growth but no seedformation process takes place. The third area to the left of the dottedline is the unstable zone in which as the only one of the three areas, aspontaneous seed formation process can take place.

[0043] The two-phase flow, or the segments of the solution containedtherein, have a concentration C₁ when entering the retention stretch,wherein the solution is transferred from a state 1 into a state 2 bymeans of a sudden reduction in temperature. State 1 can be anunsaturated state or a state which lies in the meta-stable zone, thatis, an oversaturated solution can already exist in state 1. In the caseof a lack of seeds, it is important for the invention that the state 2is in the unstable zone, which can be realised according to theinvention by a corresponding rapid temperature change. The seedformation process is introduced by transferring the solution into theunstable state and the subsequent crystallisation process is influencedby readjustment of the temperature i.e. by intentional cooling.

[0044] If a seed formation process is not required since enoughcrystallisation seeds are already present, the process can also becarried out when state 2 is in the meta-stable zone.

[0045] Targeted influence of crystal growth is only possible by means ofthe described measures. In accordance with the invention, thiscontributes substantially to the solution of the object. Very smallparticles with small diameter in the range of a few micrometres can beobtained in the unstable zone, that is, at very high oversaturation,since a great number of seeds are formed very rapidly, and hardly grow.

[0046] For this reason it is necessary to configure the structure of theretention stretch for the process according to the invention in such away that the temperature can easily be controlled so that it can easilybe heated/cooled and that great cooling rates—temperature difference pertime unit—can be attained. Hence structures in the range of a fewmillimetres or micrometres are also suitable in the retention stretch.

[0047] In the case of crystallisation according to the prior art, thedescribed manner of proceeding with the sudden shift in status variablesis avoided since temperature oscillations are caused in the solution dueto crystallisation heat being released in a short period of time, whichleads to undefined growth conditions. In contrast to this, with theprocess of the invention it is possible to exactly control thetemperature in the solution at any time by using apparatus withdimensions in the millimetre or micrometre range.

[0048] Hence the retention stretch used for the process of the inventionhas small structures, as already mentioned, wherein the greatestpossible surface/volume ratio is desired. For example, the retentionstretch is a tube, pipe or channel-shaped retention stretch with adiameter in the range from 0.5 to 10 mm, preferably from 1 mm to 2 mm,wherein according to the length of the retention stretch, which can havedimensions of between 10 cm to 200 m, preferably between 1 m to 25 m,retention times in the range of a few seconds up to several hours can berealised.

[0049] The small diameter of the retention stretch, or the greatsurface/volume ratio, implies a small quantity of solution guided in theretention stretch, which can only store a small amount of heat. For thisreason and as a result of the surface/volume ratio, the solutiondisposed in the retention stretch can be subjected to a definedtemperature from outside in a very short time, whereupon a rapidtemperature guide is rendered possible. Also due to the smalldimensions, only very small temperature gradients are observed in thesolution and hence one can assume an extensively homogenous temperaturedistribution. This is to be stressed since it is important for theeffectiveness of the crystallisation that local conditions in theretention stream do not vary and that the desired parameters are set inthe entire solution volume.

[0050] Contrary to the process used in the prior art, with the processof the invention temperature oscillations do not occur since thetemperature in the solution can be set rapidly and in a targeted mannerfrom outside, and since the seed formation process and the crystalgrowth can be exactly controlled. If the solution was transferred fromstate 1 to state 2 when using conventional crystallisers correspondingto FIG. 1, in such a way that a high oversaturation occurs, this wouldcause temperature oscillation which could not be influenced since theseed formation process which takes place in state 2 and the considerablecrystallisation heat which results with a high quantity of seeds wouldshift the state towards higher temperatures, and counter-controlling inthe form of cooling would lead to periodic temperature oscillation as aresult of the constructive dimensions of conventional crystallisers.

[0051] After passing through the retention stretch, the product mixtureis supplied to a separator in which the created crystal particles areseparated from the remaining phases, so that at the end of theproduction process, the medicament with the desired characteristics ispresent after passing through the separator.

[0052] Processes are advantageous wherein the medicament solution isprepared by dissolving the solid medicament in a solvent to form such amedicament solution.

[0053] Here, the solid medicament is dissolved in a solvent in which itcompletely dissolves at a given temperature in order to form amedicament solution.

[0054] Processes are advantageous wherein

[0055] segmentation of the solution takes place by means of a segmenterand a transport medium with the formation of plug-flow conditions.

[0056] An important advantage of this embodiment is that the two-phaseflow which exits the segmenter into the tubular retention stretch andwhich then passes through the retention stretch, does not form aparabolic speed profile (Hagen-Poiseuille law), but rather a rectangularprofile formed over time is selected. This differentiates the process ofthe invention from the processes which occur in conventionalcrystallisers, wherein a parabolic profile is selected so that the speedin the marginal areas of the pipe is reduced and ultimately becomes zeroon the wall.

[0057] As a result of this parabolic speed profile, deposits are left onthe interior wall of the pipe in conventional crystallisers, especiallyfurther-growing crystals, wherein the crystallisers ultimately becomeblocked or set.

[0058] With regard to the plug-flow conditions, we refer to FIG. 9 inwhich the flows or flow directions present in the volume segments areillustrated. The flow processes in the segments support thehomogenisation of the solution and counteract the formation ofconcentration differences in the interior and on the walls. Furthermore,blockage by means of crystalline deposits on the interior walls of theretention stretch are avoided.

[0059] Embodiments of the invention are advantageous which arecharacterised in that

[0060] the medicament solution is blended into a homogeneousprecipitation solution in a mixer with a precipitation agent and thisprecipitation solution passes through the further process.

[0061] The precipitation agent is mixed in with the medicament solutionin order to reduce the solubility of the medicament in the mixture at agiven temperature so that solid particles are formed. Here, thismedicament solution is mixed with a precipitating agent in a mixer, in aprocess step upstream of the segmenter, to produce the most homogeneousprecipitation solution possible.

[0062] To this end, micro-mixers are especially well suited since massand heat transport processes take place rapidly and efficiently in them.In the framework of the present invention, micro-mixers mean a structurewhich has dimensions in the range of 10 μm to 1 mm, preferably between25 μm to 200 μm.

[0063] For production of micronised and inhalable medicaments, a mixtureof the medicament solution and the precipitation agent into aprecipitation solution of the highest possible homogeneity is necessary.A micro-mixer with its filigree structures is especially suitable forthis purpose. When using this, the two fluids, on the one hand themedicament solution and on the other hand the precipitation agent, areseparated into individual streams by means of a micro-structure afterentering the mixer. The individual streams are, for example, lamellarand are layered with the help of channels disposed in themicro-structure in such a way that a system of thin fluid lamellaeresults wherein alternately, a fluid lamella of the medicament solutionis adjacent to a fluid lamella of the precipitation agent. Here, thelamella density in the micro-mixer is 10 to 1000, preferably 20 to 500per cm. The fluid system, which is layered in this way and whichcomprises a multitude of lamellae, is supplied to a mixing chamber inwhich mixing takes place by diffusion. Mixing according to the principleof diffusion can only take place in acceptably-short times if thestructures of the mixer, and hence the lamella thickness of theindividual streams, are small enough (preferably 10-200 μm).

[0064] The thickness of the fluid lamellae determines, in a decisivemanner, the time which is required for compensating for concentrationdifferences by diffusive mixing. If the lamella thickness is in therange of a few tens of micrometres, complete mixing and thus ahomogeneity of the precipitation solution can be realised in the entiremixed volume in a time of less than 1 second.

[0065] The micro-mixer is preferably configured so that it can easily beheated and/or cooled. Throughflow speed and temperature in themicro-mixer are selected with regard to the seed formation process sothat seed formation does not take place in the mixer.

[0066] At this point it should be stated that a multitude of devices canbe used for heating and cooling the individual described constructionelements of the micro-reactor. These are in particular wire resistanceheaters, electrical heating foils, Peltier elements and heating and/orcooling devices which operate with a temperature-control fluid such asfor example water, oil, air, nitrogen or similar. Alternatively,infra-red radiation and microwave heating can be used.

[0067] Also advantageous are embodiments of the micro-reactor wherein onthe basis of an etched plate which has an electrical heater, amicro-reactor is implemented in this plate.

[0068] Embodiments of the process are advantageous whereinsub-micrometre-sized solid particles are added to form seeds in thesegmenter, wherein it is preferred that

[0069] when using air as a transport medium, the addition of thesub-micrometre-sized solid particles preferably take place by theaddition of an adjuvant or the medicament as a powder aerosol in the airstream, and

[0070] when using a fluid transport medium, sub-micrometre-sized solidparticles are added to the transport medium in the form of adjuvant ormedicament particles, or

[0071] when using a fluid transport medium, sub-micrometre-sized solidparticles are added to the transport medium in the form of adjuvantcolloids.

[0072] The crystallisation process can be better controlled by theaddition of sub-micrometre-sized solid particles. The working range canbe expanded even into the meta-stable range (in the case of loweroversaturation conditions) by the addition of crystal seeds. With thethree aforementioned variants for adding the solid particles, the solidparticles which serve as crystallisation seeds are added to thesegmented solution from outside, i.e. by the transport medium, in thecase of the two-phase flow created in the segmenter.

[0073] Embodiments of the process are advantageous whereinsub-micrometre-sized solid particles are added in the mixer for seedformation, wherein it is preferred that the addition of thesub-micrometre-sized solid particles takes place by using aprecipitation agent which contains colloid particles.

[0074] Embodiments of the process are advantageous wherein thetemperature control in the retention stretch takes place in such a waythat a substantially constant oversaturation ΔC₁ occurs in the solution.This contributes to solving the object of the invention, namely theformation of very small particles or crystals of small diameter. FIG. 2shows how the temperature T(t) is to be controlled in order to attainconstant oversaturation over time, in the case of a parabolic course ofconcentration (FIG. 1) and assuming diffusion-controlled crystal growth(also FIG. 2).

[0075] The partial object relating to the apparatus is solved by amicro-reactor with micro-mixer, a segmenter and a retention stretch,wherein

[0076] the dimensions of the micro-mixer for separating the addedfluids, which are to be mixed, lie in the range of 10 μm to 1 mm,preferably between 25 μm to 200 μm,

[0077] the dimensions of the channels of the segmenter lie in the rangefrom 0.1 mm to 5 mm, preferably in the range between 0.2 mm and 5 mm,and

[0078] the retention stretch is configured to be tube-, pipe- orchannel-shaped with diameters of its channels in the range from 0.5 to10 mm, preferably 1 mm to 2 mm, and with the length of between 10 cm and200 m, preferably 1 m and 25 m.

[0079] It can be necessary to use a plurality of micro-reactors for theproduction of corresponding quantities of the inhalable medicament.Here, for example, 10 to 100 of such micro-reactors are combined into anarray, wherein these are operated independently of one another ordependent on one another in parallel. Production quantities of 0.5 to 2kg per day can be realised with such batteries.

[0080] Within such a battery there is a possibility for using only oneheating or cooling apparatus which heats or cools allfunctionally-similar individual devices.

[0081] As a result of its micro-structures, the micro-reactor itselfdoes not necessarily have to have small dimensions. The micro-reactorcan rather be a technical apparatus in which the functionalmicro-structures of the type described are implemented.

[0082] The partial object of the present invention relating to thepreparation of an inhalable medicament which fulfils the requirements ofan inhalable medicament is solved by a medicament with an aerodynamicdiameter of less than 20 μm, preferably less than 5 μm and greater than0.3 μm, which is characterised in that it is produced according to theprocess of the invention.

[0083] The invention is explained in greater detail with reference tovarious embodiment examples according to the drawings, which havealready been briefly described above.

[0084] The following table provides a key to the various referencenumbers used in the drawings. Reference Number Description 1 Micro-mixer2 Segmenter 3 Retention stretch 4 Aluminium profile 11 Medicamentsolution 12 Precipitation agent 13 Micro-structure 14 Mixing chamber 15Inlet opening 16 Inlet opening 17 Outlet opening 21 Precipitationsolution 22 Transport medium 23 Inlet opening 24 Inlet opening 25Two-phase flow 26 Outlet opening 27 Large pipe 28 Small pipe 131 Supplychannels 132 Supply channels

[0085]FIGS. 1 and 2 have already been explained in detail above. Thefollowing is a detailed explanation of the remaining drawings.

[0086]FIG. 3 schematically shows the structure of a micro-reactor forimplementing a first ant of the process. The micro-reactor comprises amicro-mixer 1, a segmenter 2 and a retention stretch 3. Here, themedicament solution 11 is first mixed with a precipitation agent 12 inthe micro-mixer 1 to form the most homogeneous precipitation solution 21possible. This precipitation solution 21 is supplied to the segmenter 2and is segmented with the help of a transport medium 22. The two-phaseflow which is present after passing through the segmenter is supplied tothe retention stretch 3 in which crystallisation takes place.

[0087]FIG. 4 shows the principle structure of a micro-mixer 1 with theentrance openings 15 and 16 for supply of the medicament solution 11 onthe one hand the precipitation agent 12 on the other hand, and theoutlet 17 through which the precipitation solution 21 created in themicro-mixer 1 leaves the micro-mixer. The microstructure 13, via whichthe arriving fluid streams 11 and 12 are divided into individual streamsis disposed between the entrance openings 15 and 16. The actual mixingchamber 14 is disposed above this microstructure 13. Mixing into ahomogenous solution by means of diffusion takes place in this mixingchamber 14.

[0088]FIG. 4a shows an enlargement of the microstructure 13 which liesbetween the entrance openings 15 and 16. The supply channels 131 and 132for supplying the fluid streams to the mixing chamber 14 and fordividing the arriving fluid streams into partial streams are arranged insuch a way that the partial streams which are separated by them form analternating system of thin fluid lamellae, wherein in other words, fluidlamellae of the medicament solution 11 and fluid lamellae of theprecipitation agent 12 are alternately layered.

[0089]FIG. 5 shows a schematic elevation of the structure of a segmenter2 with the entrance openings 23 and 24 and the outlet opening 26. Theprecipitation solution 21 which is supplied to the segmenter 2 via theinlet opening 23 is segmented with the help of the transport medium 22which is supplied through the inlet opening 24 and leaves the segmenter2 as a two-phase flow 25.

[0090]FIG. 6 shows a second embodiment example of a micro-mixer 1 withan integrated segmenter 2. The fluid streams which enter the micro-mixer1, the medicament solution 11 on the one hand and the precipitationagent 12 on the other hand pass through the micro-structure 13 of themicro-mixer 1 into the mixing chamber 14 and are supplied to segmenter 2after mixing in the mixing chamber 14 as an extensively homogenousprecipitation solution 21. The precipitation solution 21 is segmented inthe segmenter 2 with a second fluid which is immiscible with theprecipitation solution 21 which serves as a carrier medium 22, whereinthe thus-created two-phase flow 25 leaves the segmenter 2 through theoutlet opening 26.

[0091]FIG. 7 shows a segmenter 2 which comprises two pipes 27,28 ofwhich the smaller pipe 28 is disposed within the larger pipe 27 andcoaxial thereto. Here, the precipitation solution 21 is fed into thelarge pipe 27 via the small pipe 28 and is segmented by the transportmedium 22 which is supplied laterally through the inlet opening 24 sothat a two-phase flow 25 leaves the segmenter 2 at the end of the largepipe 27.

[0092]FIG. 8 shows a further embodiment example of a segmenter 2 wherethe supply channels which supply the precipitation solution 21 on theone hand and the transport medium 22 on the other hand form an angleΘwhich can vary between 0 and 180° and which is 90° in the embodimentexample shown in FIG. 8.

[0093]FIG. 9 shows a section of a tube-shaped retention stretch 3 incross-section. The structure of the two-phase flow 25 supplied to theretention stretch 3 is shown. This comprises fluid volumes ofprecipitation solution 21, preferably of equal sizes, which aresegmented with the help of the transport medium 22.

[0094] Also shown in FIG. 9 are the flow processes or the associatedflow directions which occur during segmenting of the precipitationsolution 21. The speeds which are determined over time give a uniformrectangular profile over the cross-section of the pipe of the retentionstretch 3. It can be seen that no deposits can form on the interiorwalls of the pipe of the retention stretch 3 under the flow conditionsprevailing in the fluid segment.

[0095]FIG. 10 shows an embodiment example of a retention stretch inperspective elevation wherein a tube-shaped retention stretch 3 is woundonto a cylindrical aluminium profile 4. The retention stretch 3 can becooled or heated via the aluminium profile 4.

[0096] As already mentioned, it is an embodiment of the process torealise a substantially constant oversaturation ΔC₁ (see FIG. 2, below)in the solution in the retention stretch. This is attained with atemperature profile wherein the temperature gradient increases over time(see FIG. 2, top, and FIG. 10, bottom).

[0097] This temperature course T(t) is realised on the one hand by thepitch of the retention stretch 3 on the aluminium block 4 (see FIG. 10,top) and on the other hand by the temperature profile T(L) in thealuminium block 4 (see FIG. 10, centre), wherein in the present examplethe temperature in the aluminium block 4 decreases in a linear mannerand the pitch of the retention stretch 3 wound on the aluminium blockincreases.

[0098] The pitch of the wound retention stretch and the temperaturecourse T(L) in the aluminium block 4 are to be adapted to eachindividual case. They are dependent on the medicament used, thesolution, the addition of solid particles as crystal seeds and theprecipitation agent, if used.

[0099] In the following text, examples are listed for the activeingredients, the adjuvants, the solvent and the precipitation agent.

[0100] The following are used as medicaments or active ingredients:

[0101] as anticholinergics; ipratropiumbromide, tiotropiumbromide,tiotropriumbromide-monohydrate,

[0102] as betasympathomimetics: bambuterol, biolterol, carbuterol,formoterol, clenbuterol, fenoterol, hexoprenalin, procaterol, ibuterol,pirbuterol, tulobuterol, reproterol, salbutamol, sulfonterol,terbutalin, orciprenalin,1-(2-fluoro-4-hydroxy-phenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,erythro-5′-hydroxy-8′-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.-butyl-amino)ethanol,1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol,

[0103] as antiallergics: disodiumchromeglicate, nedocromil, epinastin,and

[0104] as steroids: flunisolide, dexamethasone-21-isonicotinate,seratrodast, mycophenolate mofetil, pranlukast, zileuton, butixocort,budesonide, deflazacort, fluticasone, proedrol, mometasin furoate,tipredan, beclometasone (or the 16,21-dipropionate), beclomethasone,Douglas, icomethasone enbutate, cyclometasone, cloprednol, fluocortinbutyl, halometasone, deflazacort, alclometasone, cyclometasone,alisactide, prednicarbate, hydrocortisone-butyratepropionate,tixocortolpivalate, alclometaszone-dipropionate, lotrisone, canesten-HC,deprodone, fluticasone-propionate, methylprednisolone-aceponate,halopredone-acetate, mometasone, mometasone-furoate,hydrocortisone-aceponate, mometasone, ulobetasol-propionate,aminogluethimide, triamciolone, hydrocortisone, meprednisone,fluorometholone, dexamethasone, betamethasone, medrysone flucloroloneacetonide, fluocinolone acetonide, paramethasone-acetate, deprodonpropionate, aristocort-diacetate, fluocinonide, mazipredone,difluprednate, betamethasone valerate, dexamethasoneisonicotinate,beclomethasone-dipropionate, fluocortoloncapronate, formocortal,triamcinolon-hexacetonide, cloprednol, formebolone, clobetasone,endrisone, flunisolide, halcinonide, fluazacort, clobetasol,hydrocortisone-17-butyrate, diflorasone, fluocortin, amcinonide,netamethasone dipropionate, cortivazole, betamethasoneadamantoate,fluodexane, trilostan, budesonide, clobetasone, demetex, trimacinolonebenetonide,9.alpha.-chloro-6.alpha.-fluoro-11.beta.17.alpha.-dihydroxy-16.-alpha.-methyl-3-oxo-1,4-androstadiene-17.beta.-carboxyacid methylester-17-propionate.

[0105] Other medicaments produced with the process according to theinvention are montelukast and pramipexol.

[0106] As adjuvants for inhalatives, especially lactose, glucose,sucrose, mannitol and/or trehalose are used.

[0107] Examples of solvent and precipitation agents, depending on themedicaments which are to be produced, are shown in the following tables,wherein solvents and precipitation agents must be miscible.

[0108] For anticholinergics/betasympathomimetics/antiallergics: ActiveIngredient Solvent Precipitating Agents Salt forms Water, methanolAlcohols (ethanol, propanol, iso-propanol), ketones (acetone, butanone)Free bases Alcohols (ethanol, Water, methanol propanol, iso-propanol,tert.-butanol), ketones (acetone, butanone)

[0109] Active Ingredient Solvent Precipitating Agents Polars Ketones(acetone, Alcohols (methanol, butanone) ethanol) Alcohols (ethanol,Water, methanol propanol, iso-propanol, tert.-butanol), ketones(acetone, butanone) Aromatics (toluene, Alcohols (ethanol, ethylbenzene)propanol, iso-propanol) Unpolar Halogen hydrocarbons Alcohols (ethanol,(dichloromethane, propanol, iso-propanol), trichloromethane) ether(dimethylether, dioxane)

[0110] Examples of transport media are shown in the following tables,dependent on the active ingredients which are to be produced and thesolvents which are used, wherein solvents and transport media are notmiscible. Active Ingredients Solvents Transport Media Polar Water,alcohols (methanol, Fluids: ethanol iso-propanol, tert.- hydrocarbons(benzene, butanol), ketones (acetone,, petrolether, cyclohexane,propanol, butanone) decaline, benzene, toluene, xylene) Gases: air,nitrogen, carbon dioxide, helium, argon Unpolar Halogen hydrocarbonsFluids (dichloromethane, water, alcohols (methanol), trichloromethane),ether amides (formamide) (diethylether, dibutylether), Gases: aromatics(toluene, air, nitrogen, carbon ethylbenzene) dioxide, helium, argon

1. A process for the continuous production of an inhalable medicament,which comprises the following process steps: (a) producing a medicamentsolution (11), (b) segmenting the solution (11) by means of a segmenterand a transport medium (22), to yield a segmented medicament solutioncomprising alternating medicament solution and transport medium phases,(c) introducing the segmented medicament solution into a retentionstretch (3), and therein inducting and guiding crystallisation of themedicament from the medicament solution by subjecting the solution to adefined temperature, wherein seed formation is first induced by means ofa rapid temperature reduction in such a way that the solution adopts anoversaturated, meta-stable or unstable state with regard to thetemperature T and the concentration C of the medicament dissolvedtherein, and wherein crystal growth isinfluenced by intentional cooling,and (d) separating off the crystal particles from the medicamentsolution phases, using a separator, after the segmented medicamentsolution has passed through the retention stretch.
 2. A processaccording to claim 1, wherein the medicament solution (11) is preparedby dissolving solid medicament in a solvent to form a medicamentsolution (11).
 3. A process according to claim 1, wherein segmenting ofthe solution takes place by means of a segmenter and a transport medium(22) with the formation of plug-flow conditions.
 4. A process accordingto claim 1, wherein the medicament solution (11) is mixed in a mixerwith a precipitation agent (12) to form a homogenous precipitationsolution (21) and that this precipitation solution passes through thefurther process.
 5. A process according to claim 1, whereinsub-micrometer-sized solid particles are added in the segmenter to formseeds.
 6. A process according to claim 5, wherein the insertion of thesub-micrometer-sized solid particles takes place by the addition of themedicament as a dust aerosol or by the addition of an adjuvant as a dustaerosol in the air stream, when using air as a transport medium (22). 7.A process according to claim 5, wherein sub-micrometer-sized solidparticles in the form of adjuvant or medicament particles are added tothe transport medium when using a fluid transport medium (22).
 8. Aprocess according to claim 5, wherein sub-micrometer-sized solidparticles in the form of adjuvant colloids are added to the transportmedium when using a fluid transport medium (22).
 9. A process accordingto claim 4, wherein sub-micrometer-sized solid particles are added inthe segmenter to form seeds.
 10. A process according to claim 9, whereinthe addition of the sub-micrometer-sized solid particles takes place byusing a precipitation agent (12) which contains colloid particles.
 11. Aprocess according to claim 1, wherein the temperature control in theretention stretch takes place in such a way that a substantiallyconstant over saturation is present in the solution.
 12. A micro-reactorfor implementing the process of claim 1, comprising a micro-mixer, asegmenter and a retention stretch, wherein: (a) the dimensions of themicro-mixer for dividing the added fluids which are to be mixed is inthe range of 10 μm to 1 mm, preferably between 25 μm to 200 μm, (b) thedimensions of the channels of the segmenter lie in the range of 0.1 to 5mm, preferably in the range of between 0.2 mm and 5 mm, and (c) theretention stretch is configured to be tube-, pipe- or channel-shapedwith diameters of the channels in the range of 0.5 to 10 mm, preferably1 mm to 2 mm, and with a length of between 10 cm and 200 m, preferablybetween 1 m and 25 m.
 13. An apparatus for crystallizing a substance,comprising: (a) a retention stretch, having a first end and a secondend, (b) a segmenter, for producing a segmented stream which consists ofalternating segments of a solution of the substance and of a transportmedium, and for introducing said segmented stream into the first end ofsaid retention stretch, so that said segmented stream passes from saidfirst end to said second end of said retention stretch, and exists fromthe second end of the retention stretch, (c) means for cooling theretention stretch, to thereby bring about crystallization of thesubstance in the segments of solution, in the segmented stream, as saidsegmented stream passes through the retention stretch, and (d) aseparator, for separating the crystals of material from the segmentedstream as it exits from the second end of the retention stretch.
 14. Aprocess for crystallizing a substance, which process comprises thefollowing steps: (a) dissolving said substance in a solvent, to producea solution of said substance, ( b) producing a segmented stream whichconsists of alternating segments of said solution of the substance andof a transport medium, (c) introducing said segmented stream into thefirst end of a retention stretch, which retention stretch has a firstend and a second end, so that said segmented stream passes from saidfirst end to said second end of said retention stretch, and exists fromthe second end of the retention stretch, (d) cooling the retentionstretch, to thereby bring about crystallization of the substance in thesegments of solution, in the segmented stream, as said segmented streampasses through the retention stretch, and (e) separating the crystals ofmaterial from the segmented stream as it exits from the second end ofthe retention stretch.